This project targets the identification of new or novel mechanisms that modulate the effects of opiates. Animal studies tested the ability of the metabolites of l-alpha acetylmethadol (LAAM) to suppress opiate withdrawal and a human study assessed how the subjective effects of morphine were affected by rate administration. LAAM is now available as a treatment for heroin addicts, however there is little data available characterizing the efficacy of its metabolites, l-alpha-acetyl-N-normethadol (nor-LAAM) and l-alpha-acetyl-N,N-dinormethadol (dinor-LAAM) to produce acute physical dependence and to suppress opiate withdrawal. In the nondependent dog, the acute effects of LAAM and its metabolites were characteristic of strong mu opiate agonists, but 5 h after their acute administration, naltrexone elicited signs of withdrawal, indicating the development of acute physical dependence to LAAM metabolites. Of particular interest was the finding that the onset of action of intravenously administered LAAM was as rapid as the onset of effects produced by both metabolites. Thus, the rapid appearance of opiate-like effects following LAAM administration suggests that it is not a true prodrug and is an effective opiate agonist. In dogs physically dependent on morphine, nor-LAAM was 9 times as potent as either LAAM or dinor-LAAM in suppressing spontaneous withdrawal. It was concluded that the usefulness of LAAM as a treatment for opiate addiction is due the equivalent efficacies of its metabolites and the higher potency of nor-LAAM for alleviating signs of opiate withdrawal. Another study explored the pharmacokinetics of morphine administration and the resultant subjective effects. Experienced but non-dependent heroin users reported more pronounced subjective effects following rapid rather than slow intravenous administration of 10 mg morphine, which reflected its positive, rewarding properties. Concurrently, pupil constriction did not change, indicating a dissociation of subjective and miotic effects. These data indicate that faster rates of administration produce subjective effects associated with greater abuse liability.